A comprehensive and functional analysis of B-Raf signalling

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The Ras/Raf/MEK/ERK signalling pathway plays a fundamental role in various cellular processes and human disorders. The serine/threonine kinase B-Raf represents the major ERK activator and an important oncoprotein in human cancer. However, little is known about the regulatory network controlling B-Raf. Using biochemical and genetic methods, one part of the project will establish a spatio-temporal catalogue of known and novel protein-protein interactions and phosphorylation events occurring in the B-Raf signalosome. A key regulatory step in Raf activation is the Ras-induced phosphorylation of the activation loop (TVKS-motif). Surprisingly, while the importance of the Ras/Raf interaction for ERK activation was discovered more than a decade ago, the kinase phosphorylating the TVKS-motif still awaits its identification. Consequently, this kinase represents a “white spot” on our map of ERK signalling and might provide novel strategies for the inhibition of (B-)Raf. Hence, a major aim of the proposed research is to first identify and then to characterise the biological role of this kinase in vitro and in vivo. These studies will be also complemented by analysing the importance of the TVKS phosphorylation sites for B-Raf function in vivo and for malignant transformation.